Rapidly degrading formulations for reversing an attempted incapacitation

Abstract

Provided herein are formulations and methods for reversing an attempted poisoning incapacitation and may comprise administering to a subject one or more rapidly degrading unit dosage forms or a nasal spray, wherein the rapidly degrading unit dosage forms and the nasal spray comprise flumazenil. The unit dosage forms may be selected from the group consisting of a dissolving lozenge, lollipop, sublingual film, and buccal tablet and may comprise from about 0.2 to about 2 mg flumazenil and the sublingual film may degrade in the mouth over about 3 to about 6 minutes.

Description

RAPIDLY DEGRADING FORMULATIONS FOR REVERSING AN ATTEMPTED INCAPACITATIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 592,568, filed October 23, 2023, the disclosure of which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] Drug-facilitated sexual assault (which is also commonly referred to as “date rape”), where the victim is under the influence of one or more pharmacological agents, is a significant and pervasive social problem. Drug-facilitated sexual assault may involve the voluntary (“opportunistic” drug-facilitated sexual assault) or involuntary (“proactive” drug-facilitated sexual assault) ingestion of the pharmacologic agent(s). Proactive drug-facilitated sexual assault involves the perpetrator administering or “’poisoning” an intended victim with a pharmacologic agent, which may incapacitate the victim by rendering them unconscious or less capable of fending off the assailant. This poi soning may be carried out with adulteration of a beverage and / or food of the intended victim such that the victim unknowingly ingests the drug. The pharmacologic agents used for this purpose (“’incapacitating” or “’date rape” drugs) are varied, but largely fall within families of drugs that are agonists of y-amino butyric acid (GABA) receptors. GABA receptors mediate inhibitory neurologic pathways that quell consciousness and induce sleep.

[0003] GABA receptor agonists, often in the benzodiazepine (BZD) class of drugs, are often utilized by perpetrators as incapacitating drugs. The notorious incapacitating drug, Rohypnol (flunitrazepam, also known colloquially as “roofies”) is such a drug in the benzodiazepine (BZD) class of GABA agonists (specifically GABAA). Likewise, many other drugs in the benzodiazepine class of drugs, at sufficiently high doses, convey the same or similar effects of inebriation, loss of motor coordination, loss of consciousness, and even retrograde and anterograde amnesia where the victim cannot remember even the immediate events preceding the poisoning and events that occur for some time after the poisoning. The amnesia effect contributes to reasons why this class of pharmacologic agents is often used by criminals and predators as the victim’s inability to clearly remember the events immediately preceding and following the poisoning causes difficulty for the victim to report sufficient information to lawenforcement to convict the perpetrator. Beyond drags strictly in the benzodiazepine class (which include midazolam, triazolam, and diazepam), gamma-hydroxybutyrate (also known as GHB) and “Z -drags” (which include zolpidem, zaleplon and zopiclone) also act. upon theGABA receptor, and have been used by perpetrators for similar purposes.

[0004] An inappropriate dose of these incapacitating drags is known to prevent generation of sensorj' impulses or responses by the victim after consumption. For example, on consumption without any medical supervision or prescription, Rohypnol may cause harmful effects such as drowsiness, impaired motor skills, impaired judgment, reduced inhibition, dizziness and confusion. GHB has the capacity to produce intoxication and amnesia. Furthermore, a combination of the two chemical drags in a beverage may serve as a partial anesthetic, thereby causing partial or full amnesia. More often than not, these drugs may be mixed with alcoholic beverages to affect the victims to an even greater extent.

[0005] Administration of these chemical drugs in beverages results in producing the aforementioned harmful effects on a victim who may be targeted for a sexual assault. Furthermore, the harmful effects of the chemical drugs may start as soon as 15 minutes to 20 minutes after consumption, thereby providing a short time for the victim to take a reversing agent, before the victim is physically or mentally compromised by the incapacitating drag’s effects. Tire aforementioned effects become much more severe when the chemical drags are administered in heavy doses to the victim. Furthermore, administration of a heavy dose of the chemical drags may result in permanent psychological damage to the victim and in some cases an overdose may result, in instant death of the victim .

[0006] Many existing solutions to this issue have focused on quickly testing the beverage or food about to be consumed for the presence of an incapacitating drug. For example, U.S. Patent Publication No. 2011 / 0195507 provides a testing stick to be dipped into a beverage to test for the presence of flunitrazepam (also known as Rohypnol). On the one hand, this information can prevent a potential victim from consuming a beverage containing an incapacitating drag. However, if a victim has already consumed the drugged beverage or food and tests the beverage or food after the poisoning event, the victim has fewer minutes of coherence to escape the perpetrator or act due to the delay in systemic, absorption to tire train from oral dosing.

[0007] When a victim unknowingly ingests a dose of such a GABA agonist beyond a threshold dose, it can result in rapid progressive loss of motor control, loss of consciousness.dissociation, and anterograde amnesia. Following such a poisoning event, the victim, experiencing aforementioned effects due to ingestion of an incapacitating drag, will become vulnerable and unable to defend against a perpetrator’s assault (sexual or otherwise). Thus, there is an urgent need to provide a proactive intervention available to targeted individuals as a countermeasure to such attacks. For example, there is a need to provide a reversing agent to an incapacitating drug that can be administered during the 15 to 30 min treatment window. Provided herein are compositions, formulations, and methods that address this need.SUMMARY

[0008] Some embodiments of the present disclosure provide a method for reversing an attempted poisoning incapacitation, comprising administering a rapidly degrading formulation unit dosage form or nasal spray of flumazenil to a subject who has experienced a poisoning event. In some embodiments, each unit dosage form of a multiple dose flumazenil formulation comprises an administered amount of from 0.18 mg to about 0.3 mg of flumazenil with a total dose of up to 5 unit doses administer with about 10 to 40 minutes after the subject recognizes the poisoning event has occurred.

[0009] In some embodiments, the poisoning event comprises the administration of an incapacitating drug to the subject. In some embodiments, I to 5 unit dosage forms are administered within 40 minutes of the subject experiencing the poisoning event. In some embodiments, tire incapacitating drag comprises a GABA agonist. In some embodiments, the GABA agonist is selected from the group consisting of flunitrazepam, midazolam, triazolam, diazepam, gamma-hydroxybutyrate, zolpidem, zaleplon, and zopiclone. In some embodiments, the unit dosage form further comprises one or more pharmaceutically acceptable excipients. In some embodiments, the unit dosage form is selected from the group consisting of a lozenge, lollipop, sublingual film, and buccal tablet. In some embodiments, each unit dosage form comprises from about 0.8 mg to about 1.0 mg of flumazenil, and wherein the unit dosage form is a sublingual film that degrades in the mouth over 3-6 minutes. In some embodiments, the sublingual film has a diffusion flux of about 75-110 pg / cm2 / min. In some embodiments, the sublingual film has a diffusion flux of about 30-65 pg / cm2 / min. In some embodiments, the sublingual film comprises about 0.9 mg of flumazenil and one or more pharmaceutically acceptable excipients, and wherein the sublingual film has a diffusion flux of about 10-30 pg / cm2 / min.

[0010] Some embodiments of the present disclosure further provide a rapidly dissolving formulation comprising from about 0.2 to about 2 mg tlurnazenil, wherein the formulation is a lozenge, a lollipop, a sublingual film, or a buccal tablet, and wherein the formulation degrades in the mouth over about 3-6 minutes. In some embodiments, the formulation further comprises one or more pharmaceutically acceptable excipients.

[0011] Some embodiments of the present disclosure further provide a sublingual film comprising from about 0.2 to about 2 mg flumazenil, wherein the sublingual film degrades in the mouth over about 3-6 minutes. In some embodiments, the sublingual film further comprises one or more pharmaceutically acceptable excipients

[0012] Some embodiments of the present disclosure further provide a sublingual film comprising from about 0.18 to about 0.3 mg flumazenil, wherein the sublingual film degrades in the mouth over about 3-6 minutes. In some embodiments, the sublingual film further comprises one or more pharmaceutically acceptable excipients. In some embodiments, the sublingual has a diffusion flux of about 75-1 10 pg / anVrnm, In some embodiments, the sublingual film has a. diffusion flux of about 30-65 ag / cm;7mm. In some embodiments, the sublingual film comprises 0.2 mg of flumazenil and has a diffusion flux of about 10-30 ug / emt’ / mm.

[0013] Some embodiments of the present disclosure further provide a sublingual film comprising from about 0.8 to about I mg flumazenil, wherein the sublingual film degrades in the mouth over about 3-6 minutes. In some embodiments, the sublingual film further comprises one or more pharmaceutically acceptable excipients. In some embodiments, the sublingual has a diffusion flux of about 75-1 10 pg / cmNmn. In some embodiments, the sublingual film has a diffusion flux of about 30-65 pg / cm’ / min. In some embodiments, the sublingual film comprises 0.9 mg of flumazenil arid has a diffusion fiux of abou t 10-30 pg / crnrVmiri.DETAILED DESCRIPTION

[0014] Tire present disclosure provides a. pan-antidote for such an incapacitating dosing attempt that can serve as a countermeasure for a broad spectrum of potential GABA agonist intoxications. In many circumstances, when a potential victim unknowingly ingests a GABA agonist, the objective and. subjective effects of intoxication progressively intensify. The effects intensify over the period of time required for the drugs to absorb through the stomach and GI tract to the general circulation. Over time the ingested drugs achieve higher plasma and brainconcentrations. For example, oral midazolam, a fast-acting BZD drag, has an onset effect approximately 15-20 min after oral ingestion, with average peak brain effect in 30-60 min.

[0015] Therefore, the effect of ‘■incapacitating drugs” to fully incapacitate a victim is not always immediate. Accordingly, there is a therapeutic time window or margin of time (perhaps several minutes to half an hour depending on the dose of the drug and presence of other synergistic GABA acting molecules including alcohol) to intervene with a rapidly acting antidote to counteract the effect of a G ABA agonist. Specifically, there is some lapse of time between when a victim becomes aware of a suspected poisoning and when the victim becomes fully incapacitated. This window' of awareness is often forgotten by the victim without intervention of an antidote due to the amnesia effects of the GABA drug when it achieves sufficiently high plasma and brain levels.

[0016] Another complication factor that negatively affects victims’ ability to effectively react against a “poisoning” is that they may have doubt and uncertainty if they indeed have been “poisoned”. Common settings for surreptitious adulteration of beverages are m social settings where alcohol is also consumed. Tire victim may be unsure if the gradual loss of mental faculties is a result of alcohol alone or due to assault with a GABA agonist. There may be significant negative social pressure causing hesitation to raise an alarm to others for fear of false accusations or embarrassment. This hesitation unfortunately allows more critical time to pass as tlie GABA agonist takes greater effect to incapacitate the intended victim.

[0017] The victim may also have diminished capacity to physically escape the immediate situation by the time they become aware of the poisoning, as they become partially incapacitated. In the situation where a GABA agonist is surreptitiously given to a victim that has already ingested alcohol, the effect of the GABA agent is amplified as alcohol and GABA agonists have a synergistic effect because alcohol also agonizes GABA receptors at a different binding site.

[0018] Therefore, there is an acute need, preferably available without prescription (also known as over-the-counter) for an emergency self-administered antidote that can rapidly counteract a GABA agonist atempt to incapacitate an individual using GABA agonists. The present disclosure provides a dosage form of a GABA antagonist in a safe formulation that can counteract or antagonize an oral administration of a GABA agonist within a therapeuticwindow of time by being faster to the brain to effectively counteract the effects of a GABA agonist that was orally ingested.

[0019] In some embodiments, the GABA antagonist is flumazenil. Flumazenil is an imidazobenzodiazepine derivative and is a potent competitive antagonist to benzodiazepines as well as the “Z -drugs” on the central nervous system that can reverse the pharmacologic effects of benzodiazepines and “Z -drugs.” Flumazenil also partial reverses the effects of alcohol induced neurological effects as well. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA / benzodiazepine receptor complex.

[0020] In some embodiments, the GABA antagonist is selected from the group consisting of bicuculline, picrotoxin (picrotin / picrotoxinin), gabazine, sepranolone, salicylidene salicylhydrazide (SCS), and bilobalide. In some embodiments, the GABA antagonist is bicuculline.Flumazenil

[0021] Flumazenil is presently marketed only as an IV formulation as a prescription drug. It is used in hospital settings for either reversal of anesthesia induction with benzodiazepines or reversal of benzodiazepine overdose cases seen in the emergency department. Flumazenil is not practical as an oral drug since its oral availability’ is minimal. This is due to the first-pass effect leading it to be metabolized in the liver when taken orally. In order to address this problem, provided herein are dosage forms that are more amenable to administration by a route that circumvents first-pass metabolism. In some embodiments, dosage forms are selected from the group consisting of a rapidly dissolving lozenge, a buccal dissolving film / strip (e.g., held in place by the tongue), a dissolving sublingual film or strip, and a nasal spray. Small molecule drags delivered via these routes bypass “first pass” liver metabolism — allowing a far higher dose to be quickly’ delivered to the brain that can reverse GABA agonist effects.

[0022] Without being held to any particular theory’ or mechanism, another key advantage to a buccal or sublingual formulation is that such a formulation would be expected to achieve peak plasma levels sooner and reach the brain prior to, or to catch up with, an orally administered GABA agonist (a benzodiazepine). In dentistry, for example, triazolam generally reaches peak effect in 20 to 30 minutes sublingually, as compared to 30 to 45 minutes orally. Tire antidote needs to rapidly become available at the receptor target as expeditiously aspossible to counteract the poison that may have already achieved enough of a. concentration level to be eliciting a symptomatic effect.Need for Widespread A vailability

[0023] In practical application, an individual would carry a single or multiple doses of the antidote (e.g., as a sublingual strip, buccal lozenge, or nasal spray) or have it nearby when in situations where poisoning with a GABA agent is a potential risk. In the event the individual feels neurological symptoms consistent with a potential poisoning event, and before losing consciousness, the individual could rapidly administer the antidote which would enable quick reversal of the GABA agonist effects to facilitate escape of the dangerous situation.

[0024] In some embodiments, the targeted individual would have more than a single dose of this sublingual or buccal flumazenil, because tire duration of effect of the BZD or Z-drug may exceed, the duration of effect of the flumazenil (half-life is <1 hour). For example, many benzodiazepines have a longer half-life than flumazenil. Therefore, in cases of poisoning attacks, repeated doses of flumazenil may be required to prevent GABA agonist effects, once the initial dose of flumazenil wanes in effect.

[0025] lire targeted individual would ideally have sufficient quantities of flumazenil doses to counteract the poisoning until attaining access to safety and proper medical care.Sublingual Formulations

[0026] For sublingual administration, the flumazenil film or lozenge may be placed under the tongue. Without being held to any particular theory' or mechanism, the dissolved active flumazenil may reach directly into the blood stream / systemie circulation through the ventral surface of the tongue and floor of the mouth, lite reticulated vein lies underneath the oral m ucosa. Flumazenil is rapidly absorbed and transported through the facial, internal jugular and brachiocephalic veins and drained into systemic circulation . 'Hie sublingual route usually produces both a faster onset of action and improved AUG (area under curve) than orally ingested fonns, because flumazenil is absorbed through sublingual blood vessels and bypasses hepatic first-pass metabolic processes. Without being held to any particular theoiy or mechanism, the main pathway for die absorption of flumazenil into oral mucosa, may be via passive diffusion into the lipoidal membrane. For sublingual formulations, a small volume of saliva, is usually sufficient for disintegration m the oral cavity. Ihe absorption of flumazenilthrough die sublingual route is 3 to 10 times greater than oral route. Peak blood levels of most products administered sublingually are achieved within 10 to 15 minutes, which is generally much faster than when those same drags are ingested orally. Sublingual absorption is efficient The percent of each dose absorbed Is generally higher than dial achieved by means of oral ingestion.

[0027] In some embodiments, the present disclosure provides a pharmaceutical sublingual film of fiumazenil comprising about 0.2 to about 2 mg or about 0.2 to about 1 mg of fiumazenil and one or more pharmaceutically acceptable excipients with a diffusion flux of about 75-110 lig / cm / min. The pharmaceutical sublingual film of fiumazenil is in a rent dosage form comprising about 0.2 to about 2 mg or about 0.2 to about 1 mg of fiumazenil and one or more pharmaceutically acceptable excipients with a diffusion flux of about 30-65 ug / cim / mm. In some embodiments, the pharmacal sublingual film of fhmiazenn comprises about 1 mg of fiumazenil and one or more pharmaceutically acceptable excipients with a diffusion flux of about 10-30 pg / cmrVmm.

[0028] In other embodiments, the present disclosure provides a pharmaceutical sublingual film of fiumazenil comprising fiumazenil or pharmacally acceptable salts thereof as an active ingredient, and water-soluble polymeric components. The pharmaceutical sublingual film further optionally comprises of other pharmaceutically acceptable excipients selected from muco-adhesive agents, plasticizers, surfactants / non-ionic solubilizers, flavors, sweeteners and color additives. The "water soluble polymeric components" ranges about 536 to 75% w / w of the total weight of pharmaceutical sublingual film of fiumazenil, about 35% to 75% w / w of the total weight of pharmaceutical sublingual film of fi umazenil , or about 40% to 70% w Av of the total weight of pharmaceutical sublingual fihn.

[0029] in other embodiments, the water-soluble polymeric components comprise polyethylene oxide, hydrophilic cellulosic polymer (HPMC) and maltodextrin. In nother embodiments, polyethylene oxide is present in the sublingual film from about 0% to 20% by weight of the water-soluble polymeric components, about 1% to 15% by weight of the water- soluble polymeric components, or about 10% to 15% by weight of the water-soluble polymeric components. In further embodiments, hydroxypropylmethyl cellulose is present in the sublingual film from about 30% to 90 % by weight of the water-soluble polymeric components, about 40% to 90% by weight of water-soluble polymeric components, or about 70% to 85% by weight of the water-sol uble water-soluble polymeric components. In other embodiments.maitodextrin is present in the sublingual film ranges about 0% to 60% by weight of water- soluble polymeric components, about 1% to 3G% by weight of water-sohsble polymeric components, or about 5% to 15% by weight of the water-soluble polymeric components.

[0030] Some embodiments of the present disclosure provide a pharmaceutical sublingual film of fiumazenil comprising flumazeml or pharmaceutically acceptable salts thereof as an active ingredient and one or more pharmaceutically acceptable excipients delivering flumazenil dosage with a diffusion flux about 50-600 p / tnr within five minutes through the biological mucosal membranes equivalent to human oral mucosa. In some embodiments,, the pharmaceutical sublingual film of fhimazemi delivers target flux amounts with dosage amount as low as about 2 mg / imit.

[0031] The “water soluble polymer” may be a partially water-soluble polymer or predominantly water-soluble polymer, water swellable polymer or a combmation of water soluble and water swellable polymer. Tire polymers may include cellulose or cellulose derivatives. Suitable examples of water-soluble polymer include, but are not limited to, polyethylene oxide, pullulan, hydroxy propylmethyl cellulose (HPMC), Hydroxypropyl cellulose (MFC), carboxymethyl cellulose, polyvinyl alcohol. Water-swellable polysaccharides such as starch, starch deri vatives such as pol ymers of dextrose l ike maitodextrin, carrageenan, xanthan gum, locus bean gum, acacia gum, chitosan, alginates, hyaluronic acid, pectin and combinations thereof In some embodiments, the water-soluble polymers are cellulosic polymers, maitodextrin, polyethylene oxide, and combinations thereof "Hie cellulosic polymers used in combination with polyethylene oxide and maitodextrin may be selected from die group consisting of hydroxy propyl cellulose (HPC) and hydroxypropylmediyi cellulose (HPMC). Ihe polyethylene oxide polymer in combmation with a hydrophilic cellulosic polymer and maitodextrin achieves muco-adhestve, flexible, strong films

[0032] “Water soluble polymeric components” may be contained in an amount that ranges from about 5% to 75% w / w of the total weight of pharmaceutical sublingual film offlumazenil, about 35% to 75% w / w of the total weight of pharmaceutical sublingual film of fiumazenil, or about 40% to 70% w / w of the total weight of pharmaceutical sublingual film .

[0033] Polyethylene oxide, when present in the sublingual film, may be contained in an amount that ranges from about 0% to 20% by weight of the water-soluble polymericcomponents, about l%to 15% by weight of the water-soluble polymeric components, or about 10% to 15% by weight of the water-soluble polymeric components.

[0034] A plasticizer rosy be incorporated io impart flexibility, enhance elasticity and decrease brittleness. In some embodiments, the plasticizer comprises triacetine, citrate derivatives (such as trieihyl, tributyl , acetyl tributyl, acetyl triethyl, trioctyl, acetyl trioctyl, trihexyl citrate, etc.}, dibutyl sebacate, glycerol, polyethylene glycol, propylene glycol or combinations thereof. The plasticizer may be contained in an amount that ranges from about 0% to 20% wAv of the total sublingual film, about 2% to 15% wAv of the total sublingual film, or about 3% to 12% w / w of the total sublingual film.[0035} A muco-adbesive polymer for adhesion to mucosal membranes may be added, wherein the muco-adhesive polymer is selected from the group consisting of chitosan, hyaluronate, alginate, gelatin, collagen, polyfacrytic acid), poly (methacrylic acid), polyfL- lysine), polyethylene imine), polyethylene oxide), poly, (2-hydroxyethyl methacrylate), and salts or copolymers thereof

[0036] In some embodiments, the pharmaceutical sublingual film incorporates at least one Savor, chosen from natural and synthetic flavoring liquids. An illustrative list of such agents includes volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oieoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof A nonlimiting representative list of examples includes mint oils, cocoa, and citrus oils such as lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, grape, strawberry, raspbeny, cherry, plum, pineapple, apricot or other fruit flavors.

[0037] In some embodiments, the pharmaceutical sublingual film incorporates at least one sweetener, chosen from the following non-limiting list: glucose (corn syrup), dextrose, invert sugar, fiuctose, and combinations thereof saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrriuzin; Stevia Rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol, and the like Also contemplated are hydrogenated starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-metfayl-l-l-l,2,3-oxathiazm-4-one-2,2- dioxtde, particularly the potassium salt (acestiifiiree-K), and sodium and calcium salts thereof

[0038] In some embodiments, the pharmaceutical sublingual film incorporates at least one diluent which is selected from the group consisting of mannitol, microcrystaltine cellulose(MCC), lactose, and combinations thereof In some embodiments, the diluent is mannitol. In some embodiments, the pharmaceutical sublingual film incorporates at least one surfactant / noniomc solubilizer selected from the group consisting of poloxamer, polyoxyl hydrogenated castor oil. glyceryl polyethylene glycol oxystearates, fatty acid glyceryl poiygiycery i esters, polyglyceryl esters, and combinations thereof. A coloring agent (e.g., dyes) may be added. Suitable dyes for use in pharmaceutical compositions may include, for example, natural dyes such as annatto extract, anthocyanins, beta-carotene, beta. APO 8, carotenal, black currant, burnt sugar, canthaxanthin, caramel, carbo medicmals, carmine, carmine blue, carmmlc acid, carrot, chlorophyll, chlorophyllin, cochineal extract, copper-chlorophyll, copper-chlorophyllin, curcumin, curcumin / CU-chloro, elderberry', grape, hibiscus, lutein, mixed carotenoids, paprika, riboflavin, titanium dioxide, turmeric, natural colors, aronia / redfruit, beet juice colors, paprika extract, paprika oleoresin; or artificial dyes such as allura red, brilliant blue FCF, amaranth, carmoisme, fest red E, erythrosme, green S, patent blue V, ponceau 4R, quinoline yellow, red 2G, sunset yellow, FD&C yellow and tartrazine .

[0039] In some embodiments, the sublingual film may have a composition of any exemplary formulation provided in Table 1 .1 , 2. 1 , or 2.2. In some embodiments, the sublingual film may have a diffusion flux as provided in Table 1 .2.

[0040] In some embodiments, the lozenge may have a composition of any exemplary formulation provided m Table 3.1 or 3.2.Other Formulations

[0041] In some embodiments, rapidly degrading formulations of the present disclosure may be in the form of a lollipop, a nasal spray, or a buccal tablet. Such fonnulations may comprise about 0.2 to about 2 mg or about 0.2 to about 1 mg of flumazenil and one or more pharmaceutically acceptable excipients with a diffusion flux of about 75-1 10 pg / em / min. In some embodiments, the formulation comprises about 0.2 to about 2 mg or about 0.2 to about 1 mg of fiumazenil and one or more pharmaceutically acceptable excipients with a diffusion flux of about 30-65 gg / cnri / min. In some embodiments, the formulation comprises about 1 mg of flumazenil and one or more pharmaceutically acceptable excipients with a diffusion flux of about 10-30 pg / cmfonm.

[0042] In other embodiments, the present disclosure provides rapidly degrading fonnulations comprising flumazenil or pharmaceutically acceptable salts thereof as an active ingredient, andwater-soluble polymeric components. 'Hie rapidly degrading formulations further optionally comprises other pharmaceutically acceptable excipients selected from rouco-adhesive agents, plasticizers, surfactants / non-ionic solubilizers, flavors, sweeteners and color additives. 'Hie “water soluble polymeric components" ranges abou t 5% to 75% wriv of the total weight of the formulation, about 35% to 75% wAv of the total weight of the formulation, or about 40% to 70% w / w of the total wei ght of the formulation.

[0043] In other embodiments, the water-soluble polymeric components comprise polyethylene oxide, hydrophilic cellulosic polymer (HPMC) and maitodextrin In other embodiments, polyethylene oxide is present in the formulation from about 0% to 20% by weight of the water-soluble polymeric components, about 1 % to 15% by weight of die water- sohible polymeric components, or about 10% to 15% by weight of the water-soluble polymeric components. In further embodiments, hydroxypropylmethyl cellulose is present in the formulation in an amount tom about 30% to 90% by weight of the water-soluble polymeric components, about 40% to 90% by weight of water-soluble polymeric components, or about 70%> to 85% by weight of die water-soluble water-soluble polymeric components. In other embodiments, the amount of maltodextrin present in the formulation ranges from about 0% to 60% by weight of water-soluble polymeric components, about l%to 30% by weight of water- sohible polymeric components, or about 5% to 15%> by weigh t of die water-soluble polymeric components.

[0044] Some embodiments of ths present disclosure provide a formulation comprising flumazenil or a pbarmaceutica1ly acceptable salt thereof as an active ingredient and one or more pharmaceutically acceptable excipients delivering flumazenil dosage with a diffusion flux about 50-600 p / <nf within live minutes through the biological mucosal membranes equivalent to human oral mucosa. In some embodiments, the formulation delivers target flux amounts with dosage amount as low as about 2 mg / unit.

[0045] The “water soluble polymer"’ may be a partially water-soluble polymer or predominantly water-soluble polymer, water swellable polymer or a combination of water soluble and water swellable polymer. The polymere may include cellulose or cellulose derivatives. Suitable examples of water-soluble polymer include, but are not limited to, polyethylene oxide, puliulam hydioxypropylmethyl cellulose (HPMC), Hydroxypropyl cellulose (HPC), carboxymethyl cellulose, polyvinyl alcohol, Water-swellable polysaccharides such as starch, starch derivatives such as polymers of dextrose like maltodextrin, carrageenan.xanthan gum, locus bean gum, acacia gain, chitosan, alginates, hyaluronic acid, pectin and combinations thereof. In some embodiments, the water-soluble polymers are cellulosic polymers, maltodextrin, polyethylene oxide, and combinations thereof ‘Hie cellulosic polymers used in combination with polyethylene oxide and maltodextrin may be selected from tlie group consisting of hydroxy propyl cellulose (HPC ) and hydroxypropylmethyl cellulose (HPMC). 'The polyethylene oxide polymer m combination with a hydrophilic cellulosic polymer and maltodextrin achieves muco-adhesive, flexible, strong films

[0046] “Water soluble polymeric components’" may be contained in an amount that ranges from about 5% to 75% w / w of die total weight of the formulation, about 35% to 75% w / w of tlie total weight of the formulation, or about 40% to 70% w / w of the total weight of the formulation.

[0047] Polyethylene oxide, when present in the fonn elation, may be contained in an amount that mages from about 0%to 20% by weight of the water-soluble polymeric componen ts, about 1% to 15% by weight of the water-soluble polymeri c components, or about 10% to 15% by weight of the water-soluble polymeric components.

[0048] A plasticizer may be incorporated to impart flexibility, enhance elasticity and decrease brittleness. In some embodiments, the plasticizer comprises triacetine, citrate derivatives (such as triethyl, tributyl, acetyl tribatyl, acetyl triethyl, trioctyl, acetyl trioctyh trihexyl citrate, etc.), dibutyl sebacate, glycerol, polyethylene glycol, propylene glycol or combinations thereof. 'Hie plasticizer may be contained m an amount that ranges from about 0% to 20% w / w of the formulation, about 2% to 15% w / w of the formulation, or about 3% to 12% w / w of the formulation.

[0049] A rn uco-adhesrve polymer for adhesion to mucosal membranes may be added, wherein the muco-adhesive polymer is selected from the group consisting of chitosan, hyaluronate, alginate, gelatin, collagen, poiyfacryhc acid), poly(methacryhc acid), polytL- lysine), poly (ethylene imine), poly (ethylene oxide), poly, (2-hydroxyethyi methacrylate), and salts or copolymers thereof

[0050] In some embodiments, the formulation incorporates at least one flavor, chosen from natural and synthetic flavoring liquids. .An illustrative list of such agents includes volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, sterns and combinations thereof. A non-limiting representativelist of examples includes mint oils, cocoa, and citrus oils such as lemon, orange, grape, lime and grapefruit mid fruit essences including apple, pear, peach, grape, strawberiy, raspberry, cheny, plum, pineapple, apricot or other fruit flavors.[0051} In some embodiments, the formulation incorporates at least one sweetener, chosen from the following non-limiting list' glucose (com syrup), dextrose, in vert sugar, fructose, and combinations thereof; saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone coinpounds, glycynhizin; stevia, rebaudiana. (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol, and the like Also contemplated are hydrogenated starch hydrolysates and the synthetic s swweeeetteenneerr 3,6-dihydro-6-methyi-l-l-l,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfeme-K), and sodium and calcium salts thereof

[0052] hr some embodiments, the formulation incorporates at least one diluent which is selected from the group consisting of mannitol, microcrystalhne cellulose (MCC), lactose, and combinations thereof In some embodiments, the diluent is mannitol. In some embodiments, the formulation incorporates at least one surfactanvhonionic solubilizer selected from the group consisting of poloxamer, polyoxyl hydrogenated castor oil, glyceryl polyethylene glycol oxystearates, tally acid glyceryl polyglyceryi esters, polyglyceryi esters, and combinations thereof A coloring agent (e.g . dyes) may be added. Suitable dyes for use in pharmaceutical compositions may include, for example, natural dyes such as annatto extract, anthocyanins, beta-carotene, beta APO 8, carotenal, black currant, burnt sugar, canthaxanthin, caramel, carbo medicinals, carmine, carmine blue, carminic acid, carrot, chlorophyll, chloropb.yll.rn, cochineal extract, copper-chlorophyll, copper-chlorophyllin, curcumin, curcumin / CU-chloro, elderberry, grape, hibiscus, lutein, mixed carotenoids, paprika, riboflavin, titanium dioxide, turmeric, natural colors, aronia / redfruit, beet juice colors, paprika extract, paprika oleoresin; or artificial dyes such as allura red, brilliant blue FCF, amaranth, carmoisine, fast red E, erytitrosine, green S, patent blue V, ponceau 4R, quinoline yellow, red 2G, sunset yellow, FD&C yellow and tartrazine.Methods

[0053] Provided herein are methods of reversing an attempted poisoning incapacitation, comprising administering one or more rapidly degrading unit dosage forms or a nasal spray to a. subject who experiences a poisoning event, wherein the unit dosage forms and the nasal spraycomprise flumazenil. In some embodiments, the administration to the subject may be performed by the subject or by a third party.

[0054] In some embodiments, the unit dosage form may be any formulation provided herein. In some embodiments, the unit dosage form comprises an amount of from about 0.18 mg to about 0,3 mg of the flumazenil and a total dose of 1 to 5 unit dosage forms are administered within about 10 to about 40 minutes after the subject recognizes a poisoning event has occurred. In some embodiments, the unit dosage form further comprises one or more pharmaceutically acceptable excipients. In some embodiments, the unit dosage form is selected from the group consisting of a lozenge, lollipop, sublingual film, and buccal tablet.

[0055] In some embodiments, each unit dosage form comprises from about 0.8 mg to about 1 .0 mg of flumazenil, and wherein the unit dosage form is a sublingual film that degrades in the mouth over 3-6 minutes. In some embodiments, the sublingual film has a diffusion flux of about 75-110 pg / cm2 / min. In some embodiments, the sublingual film has a diffusion flux of about 30-65 pg / cm2 / min. In some embodiments, the sublingual film comprises about 0,9 mg of flumazenil and one or more pharmaceutically acceptable excipients, and wherein the sublingual film has a diffusion flux of about 10-30 pg / cm2 / min.

[0056] In some embodiments, the poisoning event comprises the administration of an incapacitating drug to the subject. In some embodiments, 1 to 5 unit dosage forms are In some embodiments, the incapacitating drag is a GABA agonist. In some embodiments, the GABA agonist is selected from the group consisting of flunitrazepam, midazolam, triazolam, diazepam, gamma-hydroxybutyrate, zolpidem, zaleplon, and zopiclone.Enumerated Embodiments

[0057] The following non-limited enumerated embodiments are only exemplary embodiments of the invention provided herein and do not limit any aspects of the present disclosure m any way.

[0058] Embodiment I- 1: A method for reversing an attempted poisoning incapacitation. comprising administering a rapidly degrading formulation unit dosage form or nasal spray of flumazenil.

[0059] Embodiment 1-2: Tire method for reversing an attempted poisoning incapacitation of Embodiment 1-1, wherein each unit dosage form of a multiple flumazenil formulation comprises an administered amount of from 0.18 mg to about 0,3 mg of flumazenil with a total dose of up to 5 unit doses taken over a 10-40 minute window7of opportunity after recognizing a poisoning event.

[0060] Embodiment 1-3: The method for reversing an attempted poisoning incapacitation of Embodiment 1-1, wherein a potential victim can take up to 5 unit dosage forms within a maximum 40 minute window to reverse a large date rape drug ingested.

[0061] Embodiment 1-4: The method for reversing an attempted poisoning incapacitation of Embodiment 1-1, wherein the rapidly degrading formulation is selected from the group consisting of a dissolving lozenge, lollipop, sublingual tab, and buccal membrane that dissolves on the inside of the cheek.

[0062] Embodiment 1-5: The method for reversing an attempted poisoning incapacitation of Embodiment 1-1, wherein each single unit dose of a flumazenil formulation is taken once, and comprises from about 0.8 mg to about 1.0 mg of flumazenil in a formulation that rapidly degrades in the mouth over 3-6 minutes.

[0063] Embodiment 1-6: The method for reversing an attempted poisoning incapacitation of Embodiment 1-5, wherein the pharmaceutical sublingual film of flumazenil comprising 0.8 to 1.0 mg of flumazenil and pharmaceutically acceptable excipients with a diffusion flux of about 75-1 10ug / cm2 / min.

[0064] Embodiment 1-7: The method for reversing an attempted poisoning incapacitation of Embodiment 1-6, wherein the pharmaceutical sublingual film of flumazenil in a unit dosage form comprising 0.8-1 .0 mg of flumazenil and pharmaceutically acceptable excipients with a diffusion flux of about 30-65pg / cm2 / min.

[0065] Embodiment 1-8: Hie method for reversing an attempted poisoning incapacitation of Embodiment 1-5, wherein the pharmaceutical sublingual film of flumazenil comprises 0.9 mg of flumazenil and pharmaceutically acceptable excipients with a diffusion flux of about 10- 30pg / cm2 / min.

[0066] Embodiment 1-9: A date rape therapeutic formulation for reversing attempted incapacitation within a treatment window, comprising a rapidly degrading formulation multiple unit dosage form having from 0.18 to 0.3 mg flumazenil in a formulation that rapidly degrades in the mouth over 3-6 minutes.

[0067] Embodiment I- 10: The date rape therapeutic formulation for reversing atempted incapacitation within a treatment window of Embodiment 1-9, wherein the pharmaceutical sublingual film of flumazenil comprising 0.18 to 0.3 mg of flumazenil and pharmaceutically acceptable excipients with a diffusion flux of about 75-1 10 pg / cm2 / min.

[0068] Embodiment 1-11: The date rape therapeutic formulation for reversing atempted incapacitation within a treatment window of Embodiment 1-10, wherein the pharmaceutical sublmgual film of flumazenil in a unit dosage form comprising 0.18-0.3 mg of flumazenil and pharmaceutically acceptable excipients with a diffusion flux of about 30-65 ug / cnr / min.

[0069] Embodiment 1-12: The date rape therapeutic formulation for reversing atempted incapacitation within a treatment window of Embodiment 1-9, wherein the pharmaceutical sublingual film of flumazenil comprises 0.2 mg of flumazenil and pharmaceutically acceptable excipients with a diffusion flux of about 10-30 pg / cm2 / min.

[0070] Embodiment 1-13: A date rape therapeutic formulation for reversing attempted incapacitation within a treatment window, comprising a rapidly degrading formulation multiple unit dosage form having about 0.8 mg to about 1.0 mg of flumazenil in a formulation that rapidly degrades in the mouth over 3-6 minutes.

[0071] Embodiment 1-14: lire date rape therapeutic formulation for reversing attempted incapacitation within a treatment window of Embodiment 1-13, wherein the pharmaceutical sublingual film of flumazenil comprising 0.8 to 1.0 mg of flumazenil and pharmaceutically acceptable excipients with a diffusion flux of about 75-1 lOpg / cnr / min.

[0072] Embodiment 1-15: The date rape therapeutic formulation for reversing attempted incapacitation within a treatment window of Embodiment 1-14, wherein the pharmaceutical sublingual film of flumazenil in a unit dosage form comprising 0.8- 1.0 mg of flumazenil and pharmaceutically acceptable excipients with a diffusion flux of about 30-65 pg / cm2 / min.

[0073] Embodiment 1-16: The date rape therapeutic formulation for reversing attempted incapacitation within a treatment window of Embodiment 1-13, wherein the pharmaceutical sublingual film of flumazenil comprises 0.9 mg of flumazenil and pharmaceutically acceptable excipients with a diffusion flux of about 10-30 pg / cm2 / min.

[0074] Embodiment II- 1: A rapidly dissolving formulation comprising from about 0.2 to about 2 mg flumazenil, wherein the formulation is a lozenge, a lollipop, a sublingual film, or a buccal tablet, and wherein the formulation degrades in the mouth over about 3-6 minutes.

[0075] Embodiment II-2: The rapidly dissolving formulation of Embodiment II-l, further comprising one or more pharmaceutically acceptable excipients.

[0076] Embodiment 11-3: A sublingual film comprising from about 0.2 to about 2 mg flumazenil, wherein the sublingual film degrades in the mouth over about 3-6 minutes.

[0077] Embodiment II-4: The sublingual film of Embodiment 11-3, further comprising one or more pharmaceutically acceptable excipients.

[0078] Embodiment 11-5: A sublingual film comprising from about 0.18 to about 0.3 mg flumazenil, wherein the sublingual film degrades in the mouth over about 3-6 minutes.

[0079] Embodiment TT-6: The sublingual film of Embodiment IT-5, further comprising one or more pharmaceutically acceptable excipients.

[0080] Embodiment II-7 : The sublingual film of Embodiment 11-13 or 14, wherein the sublingual has a diffusion flux of about 75-110 pg / cm2 / min.

[0081] Embodiment II-8: The sublingual film of Embodiment 11-13 or 14, wherein the sublingual film has a diffusion flux of about 30-65 pg / cm2 / min.

[0082] Embodiment II-9: The sublingual film of Embodiment 11-13 or 14, wherein the sublingual film comprises 0.2 mg of flumazenil and has a diffusion flux of about 10-30 pg / cm2 / min.

[0083] Embodiment II- 10 : A sublingual film comprising from about 0.8 mg to about 1.0 mg of flumazenil, wherein the sublingual film degrades in the mouth over 3-6 minutes.

[0084] Embodiment 11-11: The sublingual film of Embodiment 11-18, further comprising one or more pharmaceutically acceptable excipients.

[0085] Embodiment 11-12: The sublingual film of Embodiment 11-18 or 19, wherein the sublingual film has a diffusion flux of about 75-110 pg / cnr / min.

[0086] Embodiment 11-13: The sublingual film of Embodiment 11-18 or 19, wherein the sublingual film has a diffusion flux of about 30-65 pg / cm27min,

[0087] Embodiment 11-14: The sublingual film of Embodiment 11-18 or 19, wherein the sublingual film comprises 0.9 mg of flumazenil and wherein the sublingual film has a diffusion flux of about 10-30 ug / cm2 / min.

[0088] Embodiment 11-15: A method for reversing an attempted poisoning incapacitation, comprising administering one or more rapidly degrading unit dosage forms or a nasal spray to a subject who has experienced a poisoning event , wherein the unit dosage forms and the nasal spray comprise flumazenil.

[0089] Embodiment 11-16: lire method of Embodiment 11-15, wherein each unit dosage form comprises an amount of from about 0.18 mg to about 0,3 mg of flumazenil and wherein a total dose of 1 to 5 unit dosage forms are administered within about 10 to about 40 minutes after the subject recognizes the poisoning event has occurred.

[0090] Embodiment 11-17: The method of Embodiment 11-16, wherein the poisoning event comprises the administration of an incapacitating dmg to the subject.

[0091] Embodiment 11-18: The method of any one of Embodiments 11-15 to 17, wherein 1 to 5 unit dosage forms are administered wdthin about 40 minutes of the subject experiencing the poisoning event.

[0092] Embodiment 11-19: The method of Embodiment 11-16 or 17, wherein the incapacitating drug comprises a GABA agonist.

[0093] Embodiment 11-20: Tire method of Embodiment 11-19, wherein the GABA agonist is selected from the group consisting of flunitrazepam, midazolam, triazolam, diazepam, gamma- hydroxybutyrate, zolpidem, zaleplon, and zopiclone.

[0094] Embodiment II-21 : The method of any one of Embodiments II- 15 to 20, wherein the unit dosage form further comprises one or more pharmaceutically acceptable excipients.

[0095] Embodiment 11-22: The method of any one of Embodiments 11-15 to 21, wherein the unit dosage form is selected from the group consisting of a lozenge, lollipop, sublingual film, and buccal tablet.

[0096] Embodiment 11-23: The method of Embodiment 11-22, wherein each unit dosage form comprises from about 0.8 mg to about 1.0 mg of flumazenil, and wherein the unit dosage form is a sublingual film that degrades in the mouth over 3-6 minutes.

[0097] Embodiment 11-24: The method of Embodiment 11-23, wherein the sublingual film has a diffusion flux of about 75-110 pg / cm2 / min.

[0098] Embodiment 11-25: The method of Embodiment 11-23, wherein the sublingual film has a diffusion flux of about 30-65 ug / cnr / min.

[0099] Embodiment 11-26: The method of Embodiment 11-22, wherein the sublingual film comprises about 0.9 mg of flumazenil and one or more pharmaceutically acceptable excipients, and wherein the sublingual film has a diffusion flux of about 10-30 pg / cm2 / min.Example 1: Sublingual films con taming 1 mg, 0.8 mg & 0.2 mg doses oF flumazenil.Table 1.1: Exemplary flumazemi formulations:

[0100] Process for Preparaii on :1 . Dispersion of 11 umazeml in purified water and ethanol.2. Addition of Maltodextrin to step 1 and stirring for 3-5 minutes.3. Addition of Polyethylene oxide to step 2 and stirring for 3-5 minutes.4. Addition of Sucralose to step 3 and stirring for 3-5 minutes.5. Addition of Mamrrtol to step 4 and stirring for 3-5 minutes.6. Addition of Hydroxypropylm ethyl cellulose, polyethylene glycol / glycerol and peppermint supreme to step 5 and stirring for 5-10 minutes to form slurry.?. 'Hie slurry of step 6 was layered on polyethylene sheet and dried for 10-20 minutes atSris ':‘C to obtain the sublingual films.

[0101] The following approximate drug flux characteristics are anticipated for foe foregoing formulations:Tabb 1.2:Example 2; Additional sublingual films containing 1 mg, OH mg & 0.2 mg doses ofTable 2.1 , Exemplary flumazeml formulationslable2,2, Rirdier exeniplaix fomuizenti formulations:Example 3: Lozenges of containing 1 mg, 0.8 mg ■& 0.2 mg doses of flumazenil.

[0102] Flumazenil lozenges or loillipops can be based on powder compression or based on hard caramels. For compressed lozenges, sugar substitutes, particularly isomalt, sorbitol or polydextrose may be used, for hard sweet base fructose and / or glucose syrup may be used, as sugar-free alternative sugar substitutes, particularly sugar alcohols, such as maltitol or isomaltitol, may be used Variable amounts of sweeteners (e.g. aspartame, acesulfame, cyclamate, saccharin or xylitol) may be added. Other excipients and active substances are incorporated in the matrix and the lozenges are produced by the known production methods.

[0103] In the case of compressed powder mixtures, the excipients are weighed m accordance with the recipe and mixed with the matrix. In the case of liquid excipients or active substances, these may be added by means of a further granulating step. Then powder or granules are compressed to form lozenges. The excipients or acti ve substances may be compressed jointly or separately, as selected, in one or more layers (1-, 2- or 3-layered tablets).

[0104] In the case of hard caramels, the raw materials may be mixed according to a recipe and mixed into a heated hard caramel base. Meat-sensitive excipients and / or active substances, particularly, mucilaginous drugs, such as Icelandic moss, astringent active substances, such as alum, optional flavorings, optional colorings, mid optional stabilizers, particularly tartaric acid or citric acid are added m another step shortly be fore the final mixing and formation of the lozenges. Using these methods, sugar-free lozenges contain ing di fferent amounts of astringent and mucilaginous drugs are produced, for example, as illustrated m the following Tables:Table 3.1 ; Flmnazenil lozenge ARaw material _ Amount per lozenge (mg; flumazenil 1.0 or 0.8 or 0.2Silicone dioxide 8Lemon flavor _ 30 menthol 7 talc _ 50 macrogol _ 25 alum _ 5Isiandic moss extract 80 Total 125

[0105] The one-layer lozenge can be produced by powder compression.Table 3,2; Fhimazenil lozenge B based on hard caramel containing 5 mg alum and 80 ms Isiandic moss extract.Raw material Amount per lozenge (mg;Fluroazenil drug extract 1 .0 or 0.8 or 0.2Peach flavoring _ 15 menthol _ 0.5Citric add _ 35 sucralose 1 .5 al um _ 5Isiandic moss extract 89Total 142

[0106] The one-layer lozenge can be produced by powder compression.

Claims

CLAIMSWhat is claimed is:1 . A rapidly dissolving formulation comprising from about 0.2 to about 2 mg fiumazenil, wherein the formulation is a lozenge, a lollipop, a. sublingual film, or a buccal tablet, and wherein the formulation degrades in the mouth over about 3-6 minutes.

2. The rapidly dissolving formulation of claim 1, further comprising one or more pharmaceutically acceptable excipients.

3. A sublingual film comprising from about 0.2 to about 2 mg fiumazenil, wherein the sublingual film degrades in the mouth over about 3-6 minutes.

4. The sublingual film of claim 2, further comprising one or more pharmaceutically acceptable excipients.

5. A sublingual film comprising from about 0.18 to about 0.3 mg fiumazenil, wherein the sublingual film degrades in the mouth over about 3-6 minutes.

6. The sublingual film of claim 5, further comprising one or more pharmaceutically acceptable excipients.

7. The sublingual film of claim 5 or 6, wherein the sublingual has a diffusion flux of about 75-110 pg / cm2 / mni8. The sublingual film of claim 5 or 6, wherein the subiingual film has a diffusion flux of about 30-65 gg / cnri / mm.

9. The sublingual film of claim 5 or 6 wherein the sublingual film comprises 0.2 mg of fiumazenil and has a diffusion flux of about 10-30 gg / cm'7min .

10. A sublingual film comprising from about 0.8 mg to about 1.0 mg of fiumazenil, wherem the sublingual film degrades in the mouth over 3-6 minutes.1 1. The sublingual film of claim 10, further comprising one or more pharmaceutically acceptable excipients.

12. The sublingual film of claim 10 or 11, wherein the sublingual film has a diffusion flux13. The sublingual film of claim 10 or 1 1, wherein the subl ingual film has a diffusion flux14. The sublingual film of claim 10 or 11, wherein the sublingual film comprises 0.9 mg15. A method for reversing an attempted poisoning incapacitation, comprising administering one or more rapidly degrading unit dosage forms or a nasal spray to a subject who has experienced a poisoning event , wherein the unit dosage forms and the nasal spray comprise flumazenil.

16. The method of claim 15, wherein each unit dosage form compri ses an amount of from about 0.18 mg to about 0.3 mg of flumazenil and wherein a total dose of 1 to 5 unit dosage forms are administered within about 10 to about 40 minutes after the subject recognizes the poisoning event has occurred.

17. The method of claim 16, wherein the poisoning event comprises the administration of an incapacitating drug to the subject.

18. The method of any one of claims 15 to 17, wherein 1 to 5 unit dosage forms are administered within about 40 minutes of the subject experiencing the poisoning event.

19. The method of claim 17 or 18, wherein the incapacitating drug comprises a GABA agonist.

20. The method of claim 19, wherein the GABA agonist is selected from the group consisting of flunitrazepam, midazolam, triazolam, diazepam, gamma-hydroxybutyrate, zolpidem, zaleplon, and zopicione.

21. The method of any one of claims 15 to 20, wherein the unit dosage form further comprises one or more pharmaceutically acceptable excipients.

22. The method of any one of claims 15 to 21, wherein the unit dosage form is selected from the group consisting of a lozenge, lollipop, sublingual film, and buccal tablet.

23. The method of claim 22, wherein each unit dosage form comprises from about 0.8 mg to about 1.0 mg of fiumazenil, and wherein the unit dosage form is a sublingual film that degrades in the mouth over 3-6 minutes.

24. The method of claim 23, wherein the sublingual film has a diffusion flux of about 75- 1 10 i.ig / em2 / min.

25. The method of claim 23, wherein the sublingual film has a diffusion flux of about 30- 65 gg / cm'Vmm.

26. The method of claim 22, wherein the sublingual film comprises about 0.9 mg of fiumazenil zmd one or more pharmaceutically acceptable excipients, and wherein the sublingual film has a diffusion flux of about 10-30 pg / cm2 / mm.

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